Smoking during pregnancy has been identified as one of the major modifiable risk factors of sudden infant death syndrome (SIDS). It has been demonstrated that the risk of SIDS increases with increasing cigarette consumption. A variety of hypotheses have been proposed for explanation, including a genetic predisposition. The flavin-monooxygenase 3 (FMO3) is one of the enzymes metabolising nicotine, and several polymorphisms have already been described in this gene. Here, we studied variations in the exons and introns of the FMO3 gene by direct sequencing analysis and minisequencing in 159 SIDS cases and 170 controls. The three common variants G472A (E158K), G769A (V257M) and A923G (E308G) in the exons of the FMO3 gene were identified. The homozygote 472AA genotype occurred more frequently in SIDS cases than in controls (p = 0.0054) and was more frequent in those SIDS cases for which the mothers reported heavy smoking (p = 0.0084). This study is the first to demonstrate a gene-environment interaction in SIDS. The findings suggest that the common polymorphism G472A of FMO3 could act as an additional genetic SIDS risk factor in children whose mothers smoke. Parents who could pass on the 472A allele should be informed of the increased risk associated with smoking. Smoking mothers should be strongly advised to give up smoking during pregnancy and for at least the first year of the child's life.